Liver Transplantation for HCC Which Criteria? Jacques Belghiti - François Durand Claire Francoz Hepato-Biliary-Pancreatic Liver Surgery and Liver Transplantation Unit Hôpital Beaujon (AP-HP), Clichy - University Paris 7
Liver Transplantation Unique Transplantation for Malignancy Transplantation for Unresectable HCC Incidental tumor Cirrhosis ns
Efficiency of Liver Transplantation for HCC From Undetectable to Morphological HCC. Milan Criteria: Mazzaferro et al. N Eng J Med 1996 Single tumor < 5 cm or 2 to 3 none > 3 cm Absence of vascular invasion %) Survival ( 100 90 80 70 60 50 40 30 20 10 Mazzaferro experience 2006 : LT for HCC 0 85.8% 63.9% Criteria IN (190 pts) Criteria OUT (60 pts) 83.4% p <.0001 43.4% 0 12 24 36 48 60 72 84 96 108 120 Months ns
LT for HCC Milan Criteria Excellent results: Recommended by nearly all institution conferences on Liver Allocation in Patients with HCC. Rational for selective criteria: Recurrence of HCC after LT : disastrous prognosis!» Rapid progression due to immunosuppression i» Short life expectancy Graft should be use in oncologic patients with the same prognosis than in non HCC patient.
Vascular invasion is the most important predictive factor of recurrence of HCC after LT Hemming et al. Ann Surg,2002.
The risk of vascular invasion increases with 100 90 80 1. size of tumors 70 60 50 40 30 20 10 0 <3 cm 3-5 cm 5-8 cm > 8 cm 100 90 80 2. number of tumors 70 60 50 40 30 20 10 0 1 2 & 3 4 & 5 >5 Some Patients beyond MC (size and number of nodules) without vascular invasion could be good candidates
Expanded Criteria for HCC LT 2004-2010 Proposed criteria 5-yr survival Author (Institution) main total nodules Yao (UCSF) 6.5 cm < 8cm 2 3 80% Herrero (Pamplona) 6 cm 2-3 < 5cm 73% Kneteman (Edmonton) 7.5 cm any < 5cm 55% Silva (Valencia) < 10 cm 3 < 5 cm 69% Guiteau (Dallas) < 6cm < 9 cm 2-3 < 5cm 77% Lee (ASAN) < 6.5 cm < 6 76% Ito (Kyoto) < 10 nodules < 5cm 78% Suguwara (Tokyo) < 5 cm < 5 73% Zheng (Hangzhou) < 8 cm 72%
Number of Nodules 6 5 The metroticket paradigma the longer the trip the higher the price 4 Dual charges for extending criteria: 3 2 1 0 Inferior outcome after transplantation Negative N impact on the waiting time and wait list mortality 0 1 2 3 4 5 6 7 8 9 10 Tumor Size (cm) 75-80 % 50-75 % Expected 5-year survival 35-50 %
Patients Listed for LT: 2001-2007 400 Cirrhose alcoolique Decrease of Alcohol 350 Cirrhosis HCC 300 Cirrhose post-hépatite C 250 200 150 Autre cause Dramatic increase Retransplantation élective ou non of HCC Pathologie bilaire Hépatite fulminante 100 50 Cirrhose post-hépatite B ou B+D Stability other etiologies Autre tumeur 0 2001 2002 2003 2004 2005 2006 2007
Adult-to-adult LDLT in France 1200 100 1000 800 1043 1050 1013 1021 1015 975 882 837 791 754 755 90 80 70 60 600 400 52 48 45 49 49 42 36 50 40 30 200 0 Deceased donor Living donor 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 18 11 7 9 20 10 0
Organ shortage 12000 10000 8000 6000 4000 2000 0 2004 2005 2006 2007 2008 Data Agence de la Biomédecine Data UNOS Listed Transplanted
Increase time on the waiting list Transplantation decision Transplantation Tumor growth Vascular invasion Tumor progression Risk of Drop-out (2-4% / months) Increased with elevated AFP Llovet et al. Hepatology, 2003A
Impact of AFP on recurrence 153 patients t with cirrhosisand i HCC Progression of AFP > 15 ng/ml/month on the waiting list No : 83% Yes : 16% AFP > 300 ng/ml: 6% AFP > 300 ng/ml : 38%* In Milan : 67% In Milan : 53% Post LT recurrence : 14% Post LT recurrence : 34%* Vibert E et al. Am J Transplant 2009; 10: 129 * p < 0.05
Factors with an impact on recurrence Tumor size Number of nodules Microvascular invasion Tumor differenciation Serum alpha fetoprotein CK19 PET scan Under investigation Morphological After LT
Rate of recurrence according to alpha fetoprotein level l in the training i cohort (n = 557 patients) t Variables Hazard ratio AlFP >1000 ng/l AFP 100 ng/l p<0.001 53.0% ±6.9 26.8% ±4.7 16.2% ±2.0 Largest diameter 3 1 3-6 1.31 > 6 384 3.84 Number of nodules 1-3 1 4 and more 2.01 AFP level (ng/ml) 100 1 ]100-1000] 1000] 195 1.95 > 1000 2.57 C Duvoux et al. In press
Impact of differentiation on recurrence 105 patients transplanted over the Milan criteria Protocol biopsy pyto exclude poorly differentiated tumors No : 52 Yes : 53 5 year survival : 61% 5 year survival : 79%* DuBay D et al. Ann Surg 2011; 253: 166. * p < 0.05
LT for HCC including AFP and Differentiation Extension of morphological criteria of Milan with Low AFP and/or Good Differentiation Results of LT similar to LT within MC. Hyper-selection of patients within MC 100 90 80 70 60 50 40 30 20 10 0 <3 cm 3-5 cm 5-8 cm > 8 cm
More selective criteria of LT for HCC: Towards T d zero recurrence Stay in Radiologic Milan Criteria Exclude patients with foeto > 400 Preoperative biopsy (or resection) to exclude poor differentiate T and/or CCK component Combine LT with partial Liver Resection.
Long Term survival after LT for HCC Beaujon ( n = 322 ) 1,0 0,8 2007-2009 N=104 2001-2006 N=129 rvie cumu ulée Su 0,6 0,4 89-94 95-2000 N=74 N=15 0,2 0,0 0 12 24 36 48 60 survie patient
Conclusion Survival rate after LT for HCC should be similar to LT for other indications. In a period of drastic organ shortage, a zero recurrence rate is a desirable goal Using tools such as serum AFP and tumor differentiation help further reduce the risk of recurrence Allowing some expansion of Milan criteria Restricting some patients within the Milan criteria who are not good candidates